This project is focused on the study of the pathogenesis of HIV-associated malignancies and related diseases and the development of novel therapies for these tumors based on this understanding. Much of the work on AIDS-related malignancies has focused on tumors associated with Kaposis sarcoma-associated herpesvirus (KSHV), also called human herpesvirus-8 (HHV-8). This virus is the cause of Kaposis sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castlemans disease (MCD), tumors that most frequently occur in HIV-infected patients. We have found that hypoxia can activate latent KSHV to undergo lytic replication and that several genes of KSHV are specifically upregulated by hypoxia. We are also exploring the effects of spliced X-box binding protein-1 (sXBP-1) on activation of KSHV genes, and have found that it can directly activate production of viral interleukin-6 (vIL-6) and ORF21, a viral thymidine kinase. We are also exploring other approaches to the treatment of KSHV-associated malignancies, including pomalidomide and related cereblon-binding thalidomide analogs. We are investigating the effect of these drugs on KSHV-infected cells and the biochemical mechanisms for any effects. We have found that pomalidomide prevents the downregulation of surface expression of several immune proteins, including MHC-1 and ICAM-1. In addition, we have found that pomalidomide affects the regulation of MHC-1, ICAM-1, and B7-2 in EBV-infected and HTLV-1 infected cells and cell lines. We are studying the mechanism for these effects, their ability to affect immune function, and the effects of other drugs of interest on expression of thee surface markers. We have found that KSHV LANA is cleaved by certain caspases, and we are exploring the biology of this interaction. We are also exploring the activity of a variety of agents that affect putative steps in PEL pathogenesis for potential activity in PEL. Finally, we are conducting laboratory studies to assess the levels of cytokines and other factors in patients on clinical trials for AIDS malignancies. We have identified a group of patients with KSHV infection but without MCD who have systemic inflammatory symptoms similar to that of MCD and who have high serum levels of KSHV-encoded viral interleukin-6 (vIL-6). This represents a new disease entity of KSHV interleukin-6 cytokine syndrome (KICS).